Studies of Interaction between Hexamethonium and Lidocaine, alpha-Bungarotoxin or Decamethonium in Vitro / 대한마취과학회지

BACKGROUND: Interactions of neuromuscular blocking agents are antagonistic in a combination of depolarizing and nondepolarizing agents, additive in a combination of relative two compounds or synergistic in a combination of different two nondepolarizing agents. However, the interactions of neuromuscular blocking agents with a different site of action from each other have not been studied clearly. This study was designed to examine the interaction between hexamethonium and lidocaine, alpha-bungarotoxin or decamethonium with markedly different pre and postsynaptic sites of action. METHODS: Square wave, 0.1 Hz supramaximal stimuli or 2 Hz, 0.2 ms train of four (TOF) stimuli, was applied to the rat phrenic nerve-hemidiaphragm preparation, and the twitch height response was recorded mechanomyographically. The cumulative concentration effect and TOF ratio at each point of twitch depression after hexamethonium, lidocaine, alpha-bungarotoxin or decamethonium given were measured. The EC50 and EC95 of hexamethonium, lidocaine, alpha-bungarotoxin and decamethonium were calculated using an inhibitory sigmoid Emax model. In the experiment of each combination of two drugs, three points of the isobole for hexamethonium-lidocaine, hexamethonium-alpha-bungarotoxin and hexamethonium-decamethonium were established using ratios of 1 : 3, 1 : 1 and 3 : 1 of their EC50. Points on the line of theoretical additivity and 95% confidence intervals were calculated according to Tallarida et al. TOF ratios were observed at 75, 50 and 25% of the control twitch height value during each combination ratio of their EC50. RESULTS: Significant deviations of points on the isobole from the line of additivity to the left were found at all EC50 ratios of hexamethonium-lidocaine (P < 0.05 respectively), that to the right was found at all EC50 ratios of a hexamethonium-alpha-bungarotoxin and hexamethonium-decamethonium (P < 0.05 respectively). The magnitude of TOF fade depended upon the mixed ratios for their EC50. CONCLUSIONS: The interaction was found to be synergistic in the combination of hexamethonium- lidocaine, and antagonistic in the combination of hexamethonium-alpha-bungarotoxin and hexamethonium- decamethonium.

Neuromuscular Blocking Properties of alpha-Bungarotoxin, Decamethonium and Lidocaine in the Rat Phrenic Nerve-Hemidiaphragm Preparation / 대한마취과학회지

BACKGROUND: alpha-Bungarotoxin, decamethonium or lidocaine has a neuromuscular blocking effect. The aim of this study was to evaluate the pharmacodynamic properties of these drugs at the neuromuscular junction and the reversal effects of antagonists in vitro. METHODS: The effects of evoked twitch tension response have been studied on the isolated phrenic nerve hemidiaphragm preparation of the rat, using a single twitch (0.1 Hz) and the train of four (TOF; 2 Hz for 2 s) stimulation. The cumulative concentration effect and TOF ratio at each point of twitch depression after alpha-bungarotoxin, decamethonium or lidocaine were measured mechanomyographically. The EC50 and EC95 of alpha-bungarotoxin, decamethonium or lidocaine were calculated using an inhibitory sigmoid Emax model. The reversal effects of various doses of neostigmine, pyridostigmine or 4-aminopyridine (4-AP) to the partial neuromuscula r block produced by EC50 of alpha-bungarotoxin, decamethonium or lidocaine were determined. RESULTS: The EC50 and EC95 of alpha-bungarotoxin, decamethonium or lidocaine were 0.179 and 0.320 microgram/ml, 17.07 and 26.84 microgram/ml or 76.80 and 105.70 microgram/ml. TOF fade was produced by alpha-bungarotoxin or decamethonium but not by lidocaine. Neostigmine or pyridostigmine did not reverse the partial neuromuscular block induced by alpha-bungarotoxin, decamethonium or lidocaine. However, 4-AP produced a dose-dependent recovery of the twitch response (P < 0.05). CONCLUSIONS: alpha-Bungarotoxin, decamethonium or lidocaine produced different degree of TOF fade, and it means that this may be due to different site of action of these drugs. 4-AP reversed effectively the partial neuromuscular block induced by alpha-bungarotoxin, decamethonium or lidocaine, whereas neostigmine or pyridostigmine did not.

Evaluation of Presynaptic Action of Depolarizing Neuromuscular Blocking Agents with Single Twitch Response in Vitro / 대한마취과학회지

BACKGROUND: This study was performed to evaluate the presynaptic effects of depolarizing neuromuscular blocking drugs by using slow and fast frequencies of indirect stimulation on partial twitch depression in vitro. METHODS: A rat phrenic nerve hemidiaphragm was dissected and was mounted in an organ bath containing an oxygenated Krebs solution. The phrenic nerve was stimulated supramaximally and the twitch response (0.1 Hz) was stabilized for at least 30 minutes. T200/T1 ratio (twitch height of the 200th stimuli divided by that of the first stimuli) at frequencies of 0.2, 0.5, 1.0, and 2.0 Hz using a drug concentration which provided approximately 20% twitch depression at 0.1 Hz was calculated. To compare T200/T1 ratios with TOF ratios, a 2.0 Hz TOF response was measured immediately after the 200th stimuli at either frequency of stimulation. RESULTS: T200/T1 ratios produced by succinylcholine (SCC) and decamethonium (C10) were located between alpha-bungarotoxin (ABX) and hexamethonium (C6), however, significant differences among the four drugs were found at 2.0 Hz. The propensity for a decrease in T200/T1 ratios at 2.0 Hz might differ from this study: C6 > C10 > SCC > ABX. T200/T1 ratios at 2.0 Hz were not different from TOF ratios. CONCLUSIONS: It is concluded that small doses of C10 have a greater presynaptic activity than that of SCC, when the observed effects in this study were compared with the result of ABX acting predominantly at postsynaptic receptors and C6 acting predominantly at presynaptic receptors.

Influence of Decamethonium on the Neuromuscular Blocking Action of d-Tubocurarine in the Rat Phrenic Nerve Hemidiaphragm Preparation / 대한마취과학회지

BACKGROUND: To elucidate the mechanism of interaction between depolarizing and nondepolarizing muscle relaxants, train-of-four (TOF) fade during onset of neuromuscular blockade of d-tubocurarine (dTC) with or without decamethonium (C10) was evaluated in a rat phrenic nerve hemidiaphragm preparation. METHODS: Phrenic nerve hemidiaphragm preparations from 250~300 g Sprague Dawley rats (n=20) were suspended in a Krebs solution bubbled with 5% CO2 in O2 at 32oC. Phrenic nerves were stimulated with supramaximal stimuli of 0.2 ms duration at 0.15 Hz single twitch and 2 Hz TOF by a Grass S88 stimulator and the contractions of the hemidiaphragm were detected by a Grass FT03 force transducer then recorded. Estimation of ED50 for the dose response data were performed by a linear regression. The statistical significance of the results was determined by Wilcoxon Rank Sum test. p<0.05 was considered significant. RESULTS: Mean ED50 values of dTC and C10 calculated from the dose response relations were 7.76 microgram/ml and 0.65 microgram/ml respectively. Compared to adminstration of 2xED50 of dTC alone, TOF ratios at 75% and 50% of twitch height were markedly decreased by combination of ED50 of C10 and ED50 of dTC with statistic significance (67 +/- 1.9% vs. 46 +/- 3.1% and 36 +/- 2.5% vs. 7 +/- 2.5%). Conclusion: If fade in response to TOF stimulation represents a prejunctional effect, the results from this study suggests that the presynaptic action of C10 has some role in the mechanism of the interaction between dTC and C10 in the rat.